肾细胞癌（RCC）是成人肾癌的常见形式，其中透明细胞肾癌（ccRCC）是主要亚型。虽然手术切除仍然是局部肾细胞癌的主要治疗方法，但相当多的患者会出现疾病复发。酪氨酸激酶抑制剂（TKI）、哺乳动物雷帕霉素靶点（mTOR）抑制剂和免疫检查点抑制剂等靶向疗法的出现彻底改变了转移性肾细胞癌的治疗。然而，尽管治疗取得了进展，耐药性的出现提出了重大挑战。 RCC 的耐药机制涉及缺氧途径的破坏、PI3K/AKT/mTOR 途径的激活以及替代促血管生成因子的表达增加。此外，TKI 在溶酶体中的隔离会导致药物有效性降低和耐药性的产生。目前的研究重点是通过识别治疗效果的预测生物标志物、开发针对替代信号通路的现有疗法的新变体以及探索联合治疗方法来克服耐药性。这篇综述文章的目的是对全身治疗的耐药机制进行全面评估，并探索 RCC 的新兴治疗策略。版权所有 © 2023 国际抗癌研究所（George J. Delinasios 博士），保留所有权利。

Renal cell carcinoma (RCC) is the prevalent form of kidney cancer in adults, with clear cell renal carcinoma (ccRCC) being the predominant subtype. While surgical resection remains the primary curative approach for localized RCC, a significant number of patients encounter disease relapse. The advent of targeted therapies, including tyrosine kinase inhibitors (TKI), mammalian target of rapamycin (mTOR) inhibitors, and immune checkpoint inhibitors, has revolutionized the treatment of metastatic RCC. However, despite therapeutic advancements, the emergence of resistance poses a significant challenge. Resistance mechanisms in RCC involve the disruption of hypoxia pathways, activation of the PI3K/AKT/mTOR pathway, and increased expression of alternate proangiogenic factors. Furthermore, the sequestration of TKI within lysosomes contributes to reduced drug effectiveness and development of resistance. Current research is focused on overcoming resistance by identifying predictive biomarkers for treatment efficacy, developing novel variations of existing therapies that target alternative signalling pathways, and exploring combination therapy approaches. The objective of this review article was to provide a comprehensive assessment of resistance mechanisms to systemic therapies and explore emerging treatment strategies for RCC.Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.